(Guest Lecture): August 2023 - The Lenalidomide Patch for Myeloma: What Do We Know?

So what are we talking about today? We're talking about the lenalidomide patch for myeloma. So as lots of you may know, lenalidomide's commercial name in the United States is Revlimid, and it's commonly administered in the pill form. However, some companies are looking at applying it as a patch to the skin. So we're going to learn more about how that would work today and what the future of this patch might be through the expertise of Dr. Maroma Hussein. And now it's my pleasure to introduce him to you. He practiced at the Cleveland Clinic Foundation in Cleveland, Ohio for two decades, and during his tenure, he developed and directed the Multiple Myeloma Research Program. Dr. Hussein worked as the corporate vice president global lead of multiple myeloma for 12 years at Celgene. He is currently a professor of medicine and oncology at the University of South Florida in Tampa, Florida. He has chaired and conducted over 20 clinical trials resulting in more than 150 published peer review manuscripts, book chapters, and editorials to his credit. Dr. Hussein, we're really excited to have you here. And if you wouldn't mind just turning on your camera, there we go. And then I just wanted to make sure there wasn't anything going on. And then I'll turn the time over to you for your presentation. Thank you so much for joining us today. Oh, you're welcome. You're welcome. Thank you so much, Audrey. It really is a pleasure to discuss with you some of the changes that are happening in the world of medicine, especially trying to take some compounds. I guess you can consider Revlim with an old compound. Now it's been 15 plus years on the market and trying to modify the way you administer them to enhance its profile, enhance its tolerability, but also enhance its efficacy. So all that still is potential because a bunch of the data I'll show you is animal data. But I thought what I thought is when we start is to try to just go over the pathophysiology of multiple myeloma and where are the different pieces in that pathophysiology where image in general cell mods sort of interfere and or enhance and how that is why you would kind of go into why there is that whole work being done to enhance the image and to enhance cell mods. So should I do the share screen on my end? Yeah. All right. Let me just do that. Let me just do share. Then I'll just go to this and do it from here. Okay. Well, it's not. Oh, you know what? Okay. Here we go. Let me just. So when you look at this slide, you're going to see the bone side here on that end. And that really is a critical and important component, not just from the clinical point of view, but also from supporting myeloma and also attacking myeloma. So you would see that area has the macrophages. There is the osteoblast and osteoclast interaction where the osteoblast basically makes bone osteoclasts shave the bone off. And that's really important for just normal human bone structure to maintain its activity over the life of a person. So if he leaves the bone intact from where the osteoblast made it and you do not shave and make. So this is a continuous, what should I say? It's a continuous interaction of destroying bone and building bone. And that mechanism is because if you leave the bone made once and just leave it, the fibers in it dry out and harden up and the bone becomes brittle. So this is where in older age, people would just have a simple fall and then break their bone. It's just because the bone is brittle and the osteoblasts are not functioning as they should. And also the osteoclasts are not functioning as they should by removing the old bone. So the osteoclasts remove old bone, osteoblasts build new bone to keep the bone fresh and flexible. There is a dysregulation in this process when the myeloma cells come and basically you start seeing less buildup of the bone and more destruction of the bone. And this is where bone surveys, bone PET scans, MRIs of the bone, all that is focused on looking at this area. The macrophages have a really interesting role in this whole process where the myeloma cells manipulate the macrophages and no one knows really where is the first insult or injury that causes this disruption that happens there. It makes a bunch of chemicals and a bunch of what you would hear the name cytokines. And with those happening and being released in the system, which is the system here really ends being the microenvironment, which is the environment where the myeloma cell or the plasma cell, abnormal plasma cell that is lives in. So you would get an abnormal or aberrant stromal structure where the interaction between the plasma cell and the stroma is very strong. They really connect with each other and the stroma supports the plasma cells and the plasma cells take resources to support itself. That is one area where quite a bit of the effect of imides or cell mods in general, it breaks that ICAM and VCAM, which is basically the intracellular adhesion molecule. It's sort of the plasma cell is here, the stroma is here. Yeah, they get close to each other, but they are due to kind of leave each other and the intracellular adhesion molecule just hooks both of them together. It's a molecule that latches both of them together, an anchor in a sense. And that's where imides break out that anchor. So as soon as the myeloma is separated from this stroma or separated from that anchor that's anchoring it to the stroma, the cell becomes very vulnerable to different chemotherapeutic agents, different biologic agents become resensitized to steroids. And again, that is one way to control the plasma cell. What does happen, that's too fast. I don't know why it's doing this. Now, with those interactions between the myeloma and the stroma, it doesn't just only support it directly that way. It actually secretes growth factors, secretes chemicals, which here are called cytokines. And those different cells start to basically affect the growth of the myeloma cell. So you start having abnormal membrane interactions. These cells talk to each other. And when they talk to each other, there was a British conference about four years ago. The Germans presented in it some really amazing stuff. These cells come to eat next to each other. And when you use electron microscopy, they see like a tubing goes from one cell to the other and it injects it with whatever messages it wants it to do. And that's where cells like the natural killer cells, here you see all the way at the bottom, this defective NK cell function, those cells basically attack the myeloma cells. But those cells learn from the environment what to do. In myeloma, for some reason, they are dysfunctional. And it's not clear is the dysfunctionality inherent to them that they are dysfunctional, period, or the different chemicals and the different growth factors the myeloma makes from its environment and from itself makes those cells dysfunction. So that is a big area that a lot of people are trying to research it to see if cellular therapy can overcome this deficiency that is there. Now, with this immune dysregulation here, which you would basically T cells are not functioning appropriately, NK cells are not functioning appropriately, NK cells are, they're named natural killers, they just go and kill any cancer cell. Myeloid-derived suppressor cells, those suppress the immune system. You get the immunity of the body in two ways, in the way that fights infections reduced, and that is reduced from a cellular component, but also from the antibody component. And you probably hear all the talk about vaccine is not as effective in myeloma patients as it is in somebody who doesn't have myeloma. It's just all related to the amount of antibody secreted and specifically made to target a virus or the bacteria is not as efficient as it is in somebody who does not have myeloma. So that disrupts the immune system on two levels, the cell and the humoral or the antibody level. Blood counts because these cells live in the bone marrow are affected, less red cells, less white cells, less platelets at some point or another. And that basically kind of is or creates the hallmark for the signs and symptoms of multiple myeloma. What that does in general, as the disease goes on, you get really issues with what you call clonal evolution. So the myeloma cell basically starts to acquire genetics or abnormal genetics that result in the resistance of the disease to different therapies. So it learns what's going on and it adjusts to basically fight whatever is trying to get rid of it. And you have to remember a plasma cell, which becomes uncontrollable when it goes into myeloma. Its function in the human being is a cell that can survive different hits. It can survive hits from bacteria, hits from viruses, hits from chemicals, hits from radiation. It's a very effective cell in trying to modify itself to survive all that. That's pretty much partially how human race survived over those thousands or millions of years till we are at this point. So this cell inherits this ability with it when it becomes dysregulated or cancerous, whatever you want to mention about how that moves. One really interesting thing is for simplicity. Let's say there are two types of clones and that is usually at the beginning of the disease, it usually is to that degree. You have a dominant sensitive clone, sensitive to therapy that is, and you have a dormant minority clone. That clone is sleeping. One of the theories that one of the theories is that the dominant sensitive clone, sort of like bacteria and fungus, when you take too much, too many antibiotics, the fungus grows. And when you need that balance so that the bacteria can suppress the fungus, pretty much same concept here. When there is those majority of the cells that are sensitive are basically controlling that dormant refractory resistant clone. And it looks like that balance needs to be maintained somehow. And this is where the immune system manipulations come into play. So you can get rid of every single cell. And this is why in myeloma, the early research of just getting of every last cell you see over the years, you develop plasma cytomas, you develop aggressive disease, drug resistance, because that majority clone that was suppressing that dormant resistant clone is gone and these cells flourish. That's where the immune system comes in to kind of inhibit that flourishing. And this is where quite a bit of the research is happening around. So this kind of gives you just a quick picture of multiple myeloma in general. I can sit on this slide and talk to you for a couple of hours about it. But basically all the stuff that's happening within the bone marrow and with the interaction between the building and the destruction of the bone, those chemicals support the myeloma to latch to this trauma. As soon as it latches to this trauma, it makes all these supportive growth factors and chemicals that basically enhance or suppress the different components of the cellular immune system and also has a negative impact on the antibody system. While all this is happening, you have all that plasma cell transformation, learning what's going on and trying to transform from within to support itself so that it would not be annihilated. So why do we bother trying to kind of do anything more with the Revlimid? Like this company called StartOn, why would they focus on trying to enhance Revlimid? Why is BMS working on second, third, fourth, fifth generation of imids, what they call them now cell mods? Everyone is doing that because if you look at the statistics, and the first one is European statistics, it's not US statistics, 40% of European patients do not receive second line therapy. That data is from about four or five years ago. Maybe now it's a little better, but if you look at a little over a third of the patients don't get to receive that second line therapy, this is really a huge problem in the treatment of multiple myeloma. If you look at what happens with Revlimid, 70% or so of the patients get a dose reduction of the Revlimid. That is not a huge issue. However, though, in the first year, and that's before monoclonal antibodies were introduced by specifics, sort of the gamut of different new agents there, what happens is when you do Revlimid and Decadron, if you don't get the full dose of the Revlimid for the first nine months to a year, basically your outcome is not as good as those who get the full dose for those nine months to a year. What doesn't make sense is if you take it for 18, 24 months, the full dose, those patients don't do as well as those where you get a dose reduction. It was a retrospective study at TANAS, Demopolis and myself worked on, and it's interesting data. There is really no particular reason for why this, you and I can theorize why you have to get the full dose for a year. That's the easy part. Why reducing the dose gives those patients a better outcome. That's sort of the more difficult part of that. And then, you know, Revlimid, 50% of its use and its critical part have come from maintenance, post-bomera transplant. And that has kind of moved into also the bit of other non-transplants. Many physicians, when you take Revlimid, Darum and steroids and you start cutting on the dosages after you reach your maximum response, most of them will continue the Revlimid in the background because of its immune stabilization, maintenance and manipulations that it does. So if you find what you see is about a third of the patients in the CLGB study where the drug was approved in the United States, a third of the patients will discontinue, mainly really because of side effects. So if those patients would have taken that drug for an extra year or two years or stayed on it, you might have improved the progression-free survival of the overall study and the survival. And in this particular study, the benefit was really huge. It's 40 years as far as progression-free survival over those who did not take Revlimid, which was about two years. And there was a strong survival trend that was out there. So if you look at the decreasing of the dose, the inability to continue on it for maintenance post-transplant, those have actually bits and pieces that you can improve on. This is where the cell mods are going to target. They'll target that population for maintenance to kind of keep more patients taking the therapy, which means more patients, their immune system is maintained and or enhanced. And here, what we're trying to do with the patch is basically change the way you administer it, but change also how the levels of the drug are to minimize the side effects, enhance the safety, and potentially improve the efficacy. So when you go here, if you are in between the red line that goes across and the black line up top, that is sort of your optimal dose. But if you look at when you're taking the Revlimid by pill, the level in the blood goes way up. And then in about 12, 13 hours gets way below the minimal effective dose. So you're about 10 hours of the day below the minimal effective dose. And for a couple of hours in the day, you're at the really high dose, which is sort of what they call the C-max. The C-max is basically associated with the side effect. And the area under the curve, to some extent, is associated with side effects. If you have a huge area under the curve, it means that a lot of the drug is in there at high levels continuously. That also is associated with side effects. So the whole concept is to avoid that spike when you take a pill. And then you come to the lower part and avoid that dip so that you would not come below that effective dose. And try to stay in the middle, but not too high in the middle, more on the lower end in the middle to avoid also side effects. So with that in mind, basically is what's the minimal dose? I mean, how do you come up with that? And there is work from Celgene that is a combination of work from Celgene and work from Ken Anderson's group as well. There is that level, let me just see if you see it here, at .04. That looks like the minimal blood level that you would need to kind of see the interleukin 2 from T cells, which tells you that these T cells are really active. And this activity is sort of, that's about right for where you need to see effectivity from it with reduced toxicity. And then also you look at interferon, which tells you that the NK cells are active, and you get to right about there, somewhere around 1750 interferon picogram that would be really critical for the activity of those NK cells. So kind of that's where you would pick how much and this data is published in AACR from a couple of years ago. What you would see here is, okay, we figured what the right dose should be. And then like any other drug, especially you're changing the mode of administration is you try it on animals. And basically, group one is no drug given to the animals. Group two is given how the lenalidomide or the Rev limit has been tested by cell gene. And you would basically see that there were no responses. The disease continued to get worse, but not like as if you didn't give anything. And you'd see here the volume of the tumor, which is sort of how they assess the disease in those mice, went up here by 2500% versus with the Rev limit given intraperitoneal, which is sort of that's how Rev limit was tested originally. It grew up by almost 500%. Giving it as a continuous infusion under the skin, which is sort of we're trying to kind of see if it really makes any difference. And you see that there is a reduction of 81%. To be honest with you, in this experiment we were discussing it three or four years ago. At that time, I would have been happy to see maybe a 200% increase instead of 400 or 500% increase. It would have been great. But we had the responses. There were actually animals that responded in the IP, intraperitoneally that is, which is sort of that's how it was originally tested. There was really no responses whatsoever. Maybe stable disease for a period of time, slow growth, but at the end of the day all the animals failed. In group three, you had animals that went into complete remission and sustained that complete remission until they were sacrificed after a number of months because everybody was thinking, you know, the tumor will grow, the animals will die, and that did not happen in a small cohort of those animals. Again, you have to remember this is just animal data. A friend of mine in my training, and that was in the 80s, he left us and went to the lab to do studies. And after about a year he came out and his name is Dr. John Gutile. And John came out and I said, John, why are you coming back to see patients? He said, you know, if patients were mice, we would have cured everybody. He said, I just send these drugs out and nothing works on humans, but it works really well on mice. And it just doesn't mean anything to me anymore. So he came back to kind of get more research on patients because when it really works in people, it works. But working on mice sort of gives you an idea if it will or not, but it's not the final answer. So when you get into side effects, and the side effects, basically the white column is nothing given. It's just basically salt water. In the blue column is basically a different dose of the of the drug, which is the 48 microgram. And then the highest dose is the one is basically that longer column, which is the 144, which is pretty much the dose that we're going to study. And when you look at the different parameters for white blood counts, neutrophils, platelets, there is really not a big difference between the white, which is not giving anything in between the ones that you're giving different dose levels. So in summary, it looks like changing the method of delivery, like this last slide, might improve safety and tolerability with the mice actually showing the responses, where in this animal model, rev limit does not show a response. It shows only slow growth, but these are showing responses. And then showing literally, we think two of the 10 mice or 15 mice might have been cured because the disease would just not come back after we stopped for three months. There might be improved in efficacy. And then in humans, could the side effects be different? Could the side effects be more? You basically like a greyhound running race. Could that just keep on running and running and running, exhaust the immune system, exhaust the T cells, exhaust the NK cells? We don't know. And this is where we're basically planning on doing studies in relapsed refractory myeloma to get the dose. We're going to start with the dose that would be equivalent to about 10 milligrams, which in different studies that dose actually was effective. And for sure in maintenance, you've seen it's usually 10 and you try to go up to 15, but most of the people who went up to 15 had to go back to 10. And there are some actually good percentage that over the years dropped to somewhere between five and 10 milligrams. So the big deal is to show that really what have shown in the animal data is really true, showing improved safety and tolerability. And then the efficacy, we're hoping to see a similar efficacy. And if not better, the tolerability by itself, if you tolerate it in that 30% that drops off from maintenance and they continue on that, just by default, you're going to improve efficacy because those 30% that didn't get the benefits from continuing will get the benefits, which will increase your numbers and will show that better responses and better durability of those responses. Side effects is really going to be an interesting question. Do we exhaust the immune system or not? From the maintenance studies, looks like we do not, but again, the maintenance study is done with oral. So you get about 10, 12 hours of break during the day that you don't have the drugs or the cells can basically not work. But the trick with that is they're not working. Does that give time for the disease to learn what's going on and modulate their genomics so that they become resistant to the rafflament and so forth? That is all this needs to be answered. We might decrease resistance or we might exhaust the cells. That time will tell on that. So with here, I'll stop and take any questions from you guys. Awesome. Thank you. Sure. Okay. I'm excited. That was a great introduction. And I know you were limited on things that you could say, but I thought you did a great job at explaining why the patch could be, what potential it has, I guess, in the setting of multiple Y-Loma. I know I and several of the audience members here do have questions on terms of timing. So from what I understand, these clinical trials have only been done in the animal setting. So we would need to progress then to a phase one study, phase two, phase three, et cetera. Does the company have a timeline in terms of when that phase one study will open? Yeah. So it was targeted for October, but one of my colleagues, Dr. Nesh Gabriel in Ohio, he actually has like 27 patients lined up for that study. So this study actually is going to start probably a month earlier, assuming the paperwork and all that stuff is done, IRBs and so forth. The FDA have given the green light to the study that starts sometime in September. It will start with a, you know, a diabetes pump, an infusion pump, because the patch is probably almost a year in development. So probably be available sometime next year. So rather than delaying things and waiting until the patch is there, we're using like a subcutaneous pump to start this study. Interesting. So it will still be a continuous dosage, then it will just be through a different method of administration. Different method of administration. So we're doing it to be exactly like the patch while the patches are being developed, because one of the challenges with Revlimid, it's really a hard drug to kind of dissolve and so forth. And then you want the size of the patch to be just kind of, you slap something and you're done. Everyone, you know, from all the different surveys and asking people, asking patients, it seems like everyone would like to have a patch once a week, or maybe twice a week, not a patch every day and whatnot. Partly is because of the size of the patch. If you do it once a week, again, the very early ones were really larger size patches. So all that is in development by next year, the patches should be available and that will go there. But to kind of do the proof of concept that yes, the tolerability is better. Yes, the efficacy is at least the same, if not better. That is really going to be important. So we're starting this study. Like I mentioned, probably it will start in September, not October with patients kind of putting pressure on. I was just going to say, I'm sure the patients here today are not the only ones who are anxious for something like this to be available on the market. Yeah. Well, with your clinical trial expertise, you've been a part of many of them. What is the timeline do you think in actually having this as an FDA approved patch that people can use regularly? Oh, boy. I know it's a big question. It is. So the big deal, which I'm seeing this study, the FDA basically want to see that first part that I mentioned to you in September, October. We don't think that that part will take longer than three to six months to complete. Especially with that number of patients, we probably would complete the study enrolling in like two, three months and then waiting for the data another two, three months. So about six months, by that time, the patch should be ready. And then that would probably the interest in it would be similar to the interest. I mean, you would think with the pump, the interest, we were really worried that with the pump, the interest might not be there. But here we are. So I would probably think sometime in 26, 27 might be the time that you really kind of get all your docs and order the patch, the methodology of administration, the biologic testing, the bioequivalent studies to kind of satisfy the FDA and actually satisfy the company as well. I think probably the earliest I would imagine would be 26, early 26. But during that time, patients could participate in clinical trials. Do they plan on having it in multiple facilities? So right now, it's going to be in in Northeast Ohio that just because these guys have been on testing other compounds, not in myeloma, but in other diseases. So they're familiar with the whole mechanism and the patches and all that kind of stuff. I believe in North Carolina, there are a couple of centers that told the company they were interested. I can get you exactly where this will be. But Northeast Ohio is definitely the one that's going to start first. Awesome. Thank you. This is so exciting. There's been a couple of questions as well. Are they looking at it as a maintenance patch for after stem cell transplant or are they looking at it as an induction patch, like as part of their induction therapy? So the whole idea is to go in the area where revlimid really have been discontinued or contraindicated or patients dropped off because of the intolerance. So that is really sort of the area where it will go. So I think if you start the revlimid and then like after three months, there are significant side effects or whatever, and you're going to get off revlimid instead of getting off of it, you go with the patch. And that's this early study that we're doing in September is going to be targeting in maintenance, you know, that 30%. And that 30% is the days of CLGB. So that was at the very beginning of the use of revlimid. Sergio Girolt in his study at BMT-CTN, they had about 15%, 12, 15% that dropped off because they didn't tolerate. And that study was done several years after the first one. So people have gained the experience, but still you have that 15% that will drop mostly, uh, diarrhea, fatigue. I mean, you can go down the list, mild suppression. So the idea is that the patch will replace those areas. So it's not going to go and say, Oh, we're replacing revlimid pills. It's just going to go in the areas where revlimid is basically discontinued for one reason or another. Interesting. Now it's way too early to tell, but your gut instinct, do you think the pricing will be the same or do you think it will be significantly more? That I think actually it might be the other way around. I think the, um, the, the, the, the guys that sort of started this company, their, their, their mode was they really want to make things affordable and in, in, in widespread. So I add, and you have to also, if you have to keep in mind by 26, that have them, it's going to be a hundred percent, uh, uh, off pen. So, so, so they, they'll by just sheer knowledge of that, they have to compete with the, uh, the generic price. So it's going to be, it's actually going to be, uh, is going to be in my view, at least from listening to all these guys talking would be more affordable, way more affordable. That's encouraging. I'm glad, I'm glad they asked. Has there been any, been any discussion in, in doing this in the precursor setting of, of the high risk smoldering myeloma patients? Yeah, there has been discussions on that actually. Um, uh, it's, um, it's, it's a tricky area and actually that would make sense to use it in this area. So if it really proves to be better tolerability, less side effect profile, um, uh, less incidents of discontinuation, and even if it's as effective, not more effective, that would be a really good area to try it. Because if you look at the ECARG study, which looked at that patient population, 50% of the patients discontinued therapy because of side effects, but that 50% did better than the observation arm, even though they discontinued early on. So if you can get that 50% to not have the side effects and to continue the therapy, you probably can see a significant improvement in the outcome, meaning less transformation into multiple myeloma and so forth. So yes, that is, you know, one of the things on the, um, on the docket with the, with the discussions, but probably just kind of taking the first steps first to show that truly it's as effective, if not better, and there has better tolerability. Yeah, that's a very good question, actually. Yeah, I agree. Carol's wondering if you expect elderly frail patients to be available, or to be eligible, excuse me, for these clinical trials. Yes. Yes, the answer to that is definitely yes. Wonderful. Lots of really great questions here. I know a lot of them we covered, so I'm trying to get the ones that we haven't. Okay, this is a good question from Linda. So she's one of the patients that experiences great fatigue from Revlimid and often needs to take a rest so that her body can reset. Do you think, and I guess this is the question that we're trying to answer, right? Like, do you think that continuous therapy will make those side effects worse or better? And I know that you mentioned that's something we just have to figure out. So this is really a critical question, and this is, you're absolutely right, that's what we're trying to figure out. But there are two things. You don't get that peak in the level of the Revlimid, so that kind of cuts on some of the side effects, mainly really neutropenia, potential GI toxicity, and whatnot. Now, you don't get the trough, so maybe there is an enhancement or less genomic changes and resistant disease. I mean, all this is kind of theoretic, but then the middle part, that part, that area under the curve, that is reduced by about 60%. So with that reduction, that might actually help with the fatigue, that you might be less fatigued, and it might potentially make the fatigue less noticeable than when you have the higher area under the curve. So reducing the area under the curve might actually affect the fatigue in a positive manner. My patients, when they take Revlimid, many of them say, oh, they feel okay, this, this, the other, and for one reason or another, you stop the drug for a couple of weeks, or they're traveling, and they can't get the drug, and you say, oh, they've been on it for a number of years, two, three weeks is not a big deal. And I more than often get a call a week and a half later, and they say, oh, my God, I did not realize how tired I used to be. I'm now a new person. So even the ones that said that really, they don't know what anyone is talking about being tired, when you kind of your brain deals with it, and you just don't notice it, you develop tolerance. So when they stop it, a week and a half, two weeks later, they say, oh, my God, I'm a different person. And then they really have a hard time trying to go back on the drug because they experienced something different than what they've been feeling is normal for three or four years. So hopefully that will make a difference, that reduction in the area under the curve as well. Yeah, very well explained. Thank you. Dolores asks a good question that I saw as well as we were promoting this event. Is there any concern on who may come in contact with the patch? Will there be safety precautions when it comes to the contact? That's a huge part of the development of the patch is to avoid and have some safeguards around it that we would not run into issues because, as you know, even there are no capsules so that no one would open the capsule and use the powder and all that kind of stuff. So yes, that's part of the work on the patches to kind of have some safety guards. When you remove the patch, something either happens in the material that's lining up that was in touch with the skin or that it's going to be a specific disposal mechanism. But again, a patch versus a pill, you have much more chance of that piece of band-aid to get touched by other people and or the patient themselves. Is the idea to put it on the arm or on the stomach? Yeah, so the idea is right now is on the arm. So some people were suggesting the stomach, some people were suggesting to slap it on the back so that it's totally out of your way. You don't have to look at it and whatnot, but that will also depend on the absorption studies that they're doing, which one is really more effective. But it looks like the arm will be most likely. Thank you. We briefly touched on this, but are they still testing different dosaging like the once per week or the multiple times per week or the every day? Is that something they're looking into? That is still being done. So the idea is, and that's pretty much, Ken Anderson is involved with me in this and Dr. Ashish Shanakhan is involved with me on this as well. I mean, what we recommended to the company is that if he can get the once a week, every Sunday morning or every Saturday morning or Friday morning, you just take it and put the new one and then you're done. So the less often, the better. A week is basically what we recommended. It might end being twice a week. It depends on the size, but no one wants like a big patch, five inches by five inches. So we might end up with that daily or by week. Yeah, interesting. But it's still being tested to kind of try to kind of optimize that. Right. I know this is a hypothesis, but in your hypothesis, there's so many GI issues when it comes to Revlimid as we know chronic diarrhea is probably the number one GI issue people complain about or should complain about. I'm not saying you shouldn't complain about this. But do you think the patch would lessen these, increase these? What's just your hypothesis? I know we don't know yet, but my guess with the area under the curve being reduced, it must affect that. I don't think that diarrhea and all these side effects are basically directly from taking the pill and then the pill causes something in the stomach or the intestine. That might be part of it, but I think it's a small part. I think the part might be where you have these blood levels that at a certain level, they had to actually end affecting the writing cells, which might be in the intestine. The intestine is the largest reservoir for plasma cells. 95% of plasma cells in the body are in the intestine. 90 or 95%. So cutting, I think, hypothetically, and this is my own thinking, that question got asked in a bunch of these meetings a bunch of times, and no one really said anything specific. But in my view, I think cutting the area, the dose in the area under the curve is probably going to have some effect on the GI toxicity, mostly, if not solely, the diarrhea. It's hopeful. Now, as we also know, one of the side effects of Revlimid can be a rash. Are you concerned at all about putting a patch on the skin directly that it will erupt the whole body into a rash? No, that's a good point. So the rash with Revlimid is a couple of types. Usually happens in the first few weeks, and you get that fine, prickly, non-symptomatic rash. That's more of a show of an immune activity. That in almost 100% of the time just clears up over a period of a few weeks. Then you get the other rash that's really an allergic rash, and that part can be problematic from the pill, can be probably problematic from the patch. And Paul Richardson, and I really don't know where he is at with that, was doing a desensitization program. This is actually when I was at St. Jean. That's why we made the two and a half milligram pills, or the one milligram pills, because he wanted the desensitization program that he gives a low dose and slowly up it until he gets to the full dose, and then that body develops tolerance. That type of rash is not common, and when it happens, it's very hard to continue the Revlimid. I don't believe the patch is going to overcome that. So if you have really allergic rash, and you think if you're putting the patch on, it's going to be easier. I don't think it's going to be easier. Your point to make it 10 times worse because you're just putting it on the skin directly and whatnot, probably would be the same as if you're taking a pill. It might be delayed, so the worst part of it might be you put it on because you don't see the CMAX, so you don't jolt the system. The area under the curve is low. You can theorize that what Paul was trying to do with small dosages and slowly upping, that those maybe will develop tolerance and everything would be okay. But also, this might be one of those you just kind of slowly sneak up, and then all of a sudden you wake up one morning and you're just a red beat, and then you've got a problem. So that part will- I hope not. I hope not too. That part will sort out, but again, that type of rash is really not very common. I probably, since I started using Revlimid in the 97 or 98 in research at that time, I've probably seen five or six cases that I had to stop the drug because I just could not get around that severe rash. That's good to know. A very small rash, I mean, which happens actually in 60-70 percent of the patients that prickly elusor rash, that's more of an immune and it really shouldn't be a problem. It will clear as time goes. Yeah. Do you see this as being combined with any other drugs? Do you think there would be the patch and dexamethasone or the patch and Velcade and- Absolutely. Absolutely. I mean, it literally would be basically patch and dexamethasone patch and Velcade or carfilzomib patch. It might actually allow for a better combination and daratumumab, but just kind of go down the list. I think if really it would cut back on the myelo suppression, cut back on the fatigue, cut back on the GI, it would cater more to being combined with even more drugs that it has been difficult to combine with. So, with selenaxor, it can be a bit tough, but maybe in that kind of combination, it might kind of lessen that toughness of it that it becomes an easier drug to combine with. Yeah. Yeah. Yvette's wondering if your doctor takes you- Now, okay, let me actually rephrase this question. It's a great question, but I want to ask it more broadly. So, you talked about how in this first phase one study, they're really going to be looking at people who were not tolerating the Revlimid pill and therefore they're using the patch. Do you think that will be forever the target market or do you think they're going to try to expand into using it as a more commonly applied application? So, that's a really good question. And I think, so I think two things, and here is my political views are going to get in the middle. I mean, in the United States, if a drug works, people, physicians, that have always been off-labeled use. So, off-labeled you justify it now with insurance companies and the difficulties they give everyone, oh, it's not indicated for this, not indicated for that. Probably in Europe, that would be a big headache for the European physicians. For the US, it should be more of an insurance headache, but if you justify it, somebody's having trouble with this, trouble with that. And then somebody doesn't want to deal with these side effects to find out if they're going to get the side effects and then switch. So, I think in the US is going to be a little easier. And the reason I'm saying a little, not a whole lot easier is we're kind of switching slowly into a sort of guttery European model. So, they'll be able to prescribe it off-label and it's the same drug like the other, assuming then all what happened in animals is going to happen in humans. So, now is the company going to kind of say, oh, we're going to just do it and study it and this and study it and that depends on resources. If they have enough money to kind of go into a phase three head-to-head with that kind of stuff, non-inferiority study or even a superiority study that will really depend on resources. But if the data is really compelling, it's going to be hard for different physicians not to use it in other aspects of the disease other than the elderly, low performance. I mean, just go down the list of those. Yeah, definitely. Thank you. A question, there was a question about Europe. Do you think they will, like we said, this is such a, I'm sorry that I'm asking you such hypothetical questions. We talked about the US approval being 2026, 2027. Do you see a simultaneous European approval or do you see it being longer? No, I see a simultaneous. Europe actually, it might be actually easier to kind of maneuver and move quickly because the different studies don't have as much restrictions as the United States. So, I would see them, to be honest with you, in parallel. Awesome, thank you. And then another important question that I think will end on here. Do you think it would be easier for the kidneys, as we know Revlimid sometimes has to be significantly reduced or not used for those who have significant kidney involvement? Do you think this patch will be just as detrimental to the kidneys as the pill? So, the whole thing with the kidneys, so Revlimid is really not toxic to the kidneys. The biggest challenge with the Revlimid is a good bit of it is secreted through the, its metabolites are secreted through the kidneys. So, I think with the reduction of the area under the curve, it's sort of as if you're giving a reduced dose already for eliminating the CMAX in a sense that you reduce the dose. So, I think it would be an easier drug to maneuver in kidney patients. Joe McHale did a study in Precog in patients with renal failure and whatnot and tried to kind of figure out does he have to reduce the dose or not. And in his study, even though it was limited to some degree, he came up to this conclusion that it doesn't really matter. And I believe I haven't seen it in print, I've seen some of the drafts for it being written up, but they came up with a conclusion that you don't need to reduce the dose of the Revlimid in patients with renal dysfunction or whatever. And there was a particular cutoff, you know, they're like greater than 30 mLs per minute of, as a measure of the renal functionality. To be honest with you, me personally, I tend to reduce the dose and I tend to be careful. It's pain in the neck because as you treat the myeloma, the renal function tends to improve. So you can't continue to give that reduced dose because in a sense you're giving potentially an ineffective dose. You'll have to kind of increase. So if the patient is willing to kind of just get checked off and you play around with it, it will work. So the patch might overcome some of that by having a lower area under the curve, no C max's, then it will be relatively safer and also less exhausting for the physician and the patient to adjust the dose. Yeah, very well said. Thank you. Well, we did not get to all the questions because there's a lot of people here, but we are grateful for all the questions that were asked. And thank you, Dr. Hussein, for spending this time with us. You're a brilliant physician and answered a lot of really great questions. We'll have to have you back in a couple of years to give us an update. Definitely. It's your time now to just give any closing remarks that you would like to. And thank you again for spending time with us today. You're welcome. Thank you so much, Audrey. And I really appreciate the invite and appreciate you guys' interest in hearing about trying to make an old compound a little more tolerable. Really, the bottom line is if the animal data translates into humans, which there is an if there, it would be a huge addition to the therapy of multiple myeloma. So you'd get about 30% potentially altogether relapsed refractory, newly diagnosed maintenance, that kind of population that loses out on the use of Revlimid would be incorporated there. We're a couple of years away, I mean, two, three years from the drug being really on the market, assuming it's successful and translates. But again, there are other drugs too that are coming. Iberdermide is on the radar screen now with studies going pretty well and pretty fast. So Paul Richardson just gave a talk a couple of weeks ago on it. So it really is the whole field is moving very quickly, advancing. And the idea of you have to take toxic therapy to kind of get to a good result is sort of slowly. Fading away. So hang in there. And I think you all should do really well, especially with the doctors here in the United States. Thank you. I really appreciate your time. You're free to go. I'll keep my audience for just a little bit longer. But thanks so much. Nice to meet you. Wonderful. Well, that certainly gets me excited for the future. I know there's a lot that we don't know. I know there's a lot of our questions that we asked and didn't have super solid answers to, but the hope, I hope, remains with you. You can know that there's lots of myeloma drugs that are being approved. We just had L-ranitamab approved, not technically FDA approved, but FDA fast-tracked. You'll see an article on our website about that soon. We had Telketamab, which is a new by-specific antibody that was approved. These are huge groundbreaking medicines that are able to improve myeloma patient quality of life, longevity, et cetera. And the efficacy against myeloma is just amazing. So I'm really excited for the future. And I hope that you are as well. I hope that you carry on the hope of this awesome research that's being done with you. We are meeting tomorrow to talk about by-specifics. We're specifically talking about toclostomab, but I wouldn't be surprised if there's questions even from me about Telketamab, which is that new by-specific antibody that targets GPRC5D. Toclostomab targets BCMA. And so that's also what CAR-T targets and things that we're familiar with. Then Tuesday, August 22nd, it says Florida Community Chapter. It's for everybody. It's talking about gaps in myeloma education and how can you navigate to find resources that will help you fill those gaps? And how do you get answers to your pertinent and important questions? And then Thursday, August 24th is our Black Myeloma Health Chapter. This month, we're going to be having a conversation talking about challenges, obstacles, and surprises together. Willing to sign up for any of those events and even more events that I have not mentioned is found at the bottom of the slide and will be included in the follow-up email. A special thank you to our sponsors, Amgen, Avie, Adaptive Biotechnologies, Janssen Oncology, and Genentech and Bristol-Meier Squibb. I see a note here. There are GPRC5D CAR-Ts in early trials. I am aware of that. Thank you. I just was talking about the FDA approved ones, but excellent note that that's even more helpful that there are other CAR-Ts available as well that are going to be hopefully approved if they go well. Thank you to each of you. This is such an informed and educated group and you're so kind and respectful. I really appreciate you. Appreciate you taking the time out of your day and just your participation. It matters to me a lot and I hope you have a great rest of your day, everyone. Take care. Bye-bye.